Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/28—Compounds containing heavy metals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to metal complexes which may be used in treating cancer.
• the invention relates to silver metal complexes that are incorporated within biodegradable materials, such as nanoparticles, and are used in treating cancer.
• Silver has long been used for its antimicrobial properties. This usage predates the scientific or medical understanding of its mechanism. For example, the ancient Greeks and Romans used silver coins to maintain the purity of water. Today silver is still used for this same purpose by NASA on its space shuttles. Treatment of a variety of medical conditions using silver nitrate was implemented before 1800. A 1% silver nitrate solution is still widely used today after delivery in infants to prevent gonorrheal ophthalmia. Since at least the later part of the nineteenth century, silver has been applied in a variety of different forms to treat and prevent numerous types of bacteria related afflictions.
• Paclitaxel IUPAC name ⁇ -(benzoylamino)- ⁇ -hydroxy-,6,12b-bis (acetyloxy)-12- (benzoyloxy)-2a,3,4,4a,5,6,9,10,l l,12,12a,12b-dodecahydro-4,l l-dihydroxy-4a,8,13,13- tetramethyl-5-oxo-7,l l-methano-lH-cyclodeca(3,4)benz(l,2-b)oxet-9-ylester,(2aR-(2a- ⁇ ,4- ⁇ ,4a- ⁇ ,6- ⁇ ,9- ⁇ ( ⁇ -R*, ⁇ -S*),l l- ⁇ ,12- ⁇ ,12a- ⁇ ,2b- ⁇ ))-benzenepropanoic acid), into PLGA nanoparticles for drug delivery.
• Paclitaxel IUPAC name ⁇ -(benzoylamino)- ⁇ -hydroxy-,6,12b
• PEGP poly(di(ethyl glycinato) phosphazene)
• PEAP poly(di(ethyl alaninato) phosphazene)
• one aspect of the invention is to provide a compound for treating cancer, the compound comprising a metal complex having predetermined characteristics, and which may be incorporated into a polymeric nanoparticle or other delivery system for delivering the metal complex for action on tumor cells.
• the metal complex is a silver(I) salt, a silver(I) macrocyclic metal complex, a silver(I) N- heterocyclic carbene or mixtures thereof.
• the silver(I) macrocyclic metal complex is: wherein each R is independently selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, a peptide, or null, wherein X 1 , X 2 and X 3 are independently either sulfur or nitrogen, and when X 1 , X 2 or X 3 is sulfur then R is null, wherein the macrocyclic ligand comprised of carbon, R 1-3 , and X 1-3 , represents L, wherein Y is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br,
• R 1 and R 2 are selected from the group consisting of a halide, a proton, an alkyl, an ether, an alcohol, a nitro, a cyano, and a carboxylic acid
• R 3 and R 4 are selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide
• X is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I.
• R 1 and R 2 are selected from the group consisting of a halide, a proton, an alkyl, an ether, an alcohol, a nitro, a cyano, and a carboxylic acid
• R 3 and R 4 are selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide
• X is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I.
• R 1-4 can are selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide, and wherein X is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I.
• a method of treating cancerous cells in a mammal includes the steps of: administering an effective amount of a silver(I) metal salt incorporated into a biodegradable polymeric nanoparticle.
• a method of treating cancerous cells in a mammal includes the steps of: administering an effective amount of a macrocyclic silver(I) complex, the macrocyclic complex comprising:
• each R is independently selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, a peptide, or null, wherein X 1 , X 2 and X 3 are independently either sulfur or nitrogen, and when X 1 , X 2 or X 3 is sulfur then R is null, wherein the macrocyclic ligand comprised of carbon, R 1-3 , and X 1-3 , represents L, wherein Y is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I, or may represent L, and wherein Y represents L, then the counter anion is selected from the group consisting of NO 3 " , OAc “ , SCN “ , BF 4 “ , OTf “ , SO 4 " , Cl “ , Br “ , and I “ .
• a method of treating cancerous cells in a mammal includes the steps of: administering an effective amount of a N-heterocyclic silver(I) complex, the N- heterocyclic complex comprising:
• R 1 and R 2 are selected from the group consisting of a halide, a proton, an alkyl, an ether, an alcohol, a nitro, a cyano, and a carboxylic acid
• R 3 and R 4 are selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide
• X is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I.
• a method of treating cancerous cells in a mammal includes the steps of: administering an effective amount of a N-heterocyclic silver(I) complex, the N- heterocyclic complex comprising:
• R 1 and R 2 are selected from the group consisting of a halide, a proton, an alkyl, an ether, an alcohol, a nitro, a cyano, and a carboxylic acid
• R 3 and R 4 are selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide
• X is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I.
• a method of treating cancerous cells in a mammal includes the steps of: administering an effective amount of a N-heterocyclic silver(I) complex, the N- heterocyclic complex comprising:
• R 1-4 can are selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide, and wherein X is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I.
• a method of treating cancerous cells in a mammal includes the steps of: administering an effective amount of a N-heterocyclic silver(I) complex, the N- heterocyclic complex comprising: wherein R 1-4 can are selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide, and wherein X is selected from the group consisting of NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , Cl, Br, and I.
• FIG. 1 shows a graph of the activity of compounds in the treatment of the ovarian cancer cell line NuTu- 19;
• FIG. 2 shows a chart comparing anti-proliferative effects of formula 23, cisplatin and carboplatin on A375 melanoma;
• FIG. 3 shows a graph measuring the percent control growth of formula 23, cisplatin and carboplatin on A375 melanoma at various concentrations;
• FIG. 4 shows a chart comparing anti-proliferative effects of formula 23, cisplatin and carboplatin on ACHN renal carcinoma;
• FIG. 5 shows a graph measuring the percent control growth of formula 23, cisplatin and carboplatin on ACHN renal carcinoma at various concentrations;
• FIG. 6 shows a chart comparing anti-proliferative effects of formula 23, cisplatin and carboplatin on HT 1376 colon carcinoma
• FIG. 7 shows a graph measuring the percent control growth of formula 23, cisplatin and carboplatin on HT1376 colon carcinoma at various concentrations.
• metal compounds including metal complexes
• biodegradable nanoparticles such as for use in the treatment of cancer
• the present invention comprises, but is not limited to silver(I) metal complexes as simple salts, silver(I) macrocyclic metal complexes, and silver(I) N-heterocyclic carbenes (NHCs) incorporated within biodegradable nanoparticles for the treatment of cancer.
• N-heterocyclic carbenes N-heterocyclic carbenes
• Nanoparticles may generally vary in size from 10 nm to 1000 nm. These sub-micron sized particles possess certain distinct advantages over microparticles.
• Nanoparticles including nanospheres, unlike microspheres, can be used to directly target the tissues via systemic circulation or across the mucosal membrane. This targeting is possible as a result of the capacity of these nanoparticles to be endocytosed by individual cells. It has also been observed that nanoparticles administered intravenously are taken up by cells of mononuclear phagocyte system, mainly in the Kuppfer cells. Such nanoparticles are rapidly cleared from the blood and are usually concentrated in the liver, spleen and blood marrow.
• the therapeutic agent is dissolved, encapsulated, entrapped or chemically conjugated to the nanoparticle matrix depending on the method of fabrication of the device.
• the drug is physically and uniformly incorporated and dispersed within a nanosphere matrix.
• the drug formulated in such a polymeric device is released by diffusion through the polymeric matrix, erosion of the polymeric matrix or by a combination of diffusion and polymer erosion mechanisms.
• biodegradable, polymeric nanoparticles including poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(lactic-co-glycolic acid) (PLGA) are used.
• nanoparticles were investigated primarily for the delivery of simple drug molecules.
• nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in the controlled release of drugs, as carriers of DNA in gene therapy, their ability to target particular organs and tissues and in their ability to encapsulate and delivery peptides, proteins and genes through a peroral route of administration.
• the methods used to prepare nanoparticles can be broadly classified into two: (1) dispersion of the preformed polymers, and (2) polymerization of monomers, however; several different variations of each of the above methods have been attempted to optimize the product formulation.
• Some of the more common variations of the first method that have been used to prepare nanoparticles include (a) solvent evaporation method, (b) spontaneous emulsification/solvent diffusion method and salting out/emulsification-diffusion method.
• a common theme observed in these cases is an attempt to remove the organic solvent in a controlled manner thereby bringing about the precipitation of the polymeric particles.
• the encapsulation of the drug is carried out by dissolving the drug in the organic phase containing the polymer or an inner aqueous phase depending on the relative hydrophilicity and solubility of the drug.
• the polymer In case of polymeric nanoparticles prepared by polymerization of monomers, the polymer usually has a lower solubility in the polymerization medium compared to the monomer. This results in the precipitation of the polymer with an increase in the molecular weight of the polymer.
• a control over the particle size is achieved by altering parameters such as rate of mechanical stirring, type and concentration of surfactant and/or stabilizer used, pH of the polymerization medium, etc.
• the drug can be encapsulated within the nanoparticles either during the polymerization process or post-polymerization.
• One group of nanoparticles includes polyphosphazenes [PR 2 N] n .
• Polyphosphazenes are versatile polymers because they can be functionalized with a large variety of R groups by simply displacing the chlorides of the parent [PCl 2 N] n polymer.
• the water sensitivity of the polyphosphazene can be varied from water-stable to water- sensitive by the choice of the substituent. In general, most R groups that are bound to the phosphazene backbone via a P-N bond are water sensitive and those that are bound via a P-O bond are water stable.
• the compounds useful for the treatment of cancer include silver(I) salts that are incorporated within the biodegradable nanomeric polymers including PLA, PGA, and PLGA are generally represented by formula 1 or by formula 2:
• X is represented by NO 3 , OAc, SCN, BF 4 , OTf, or SO 4 and wherein Y is represented by Li, Na, or K and X is represented by Cl, Br, or I.
• each R can vary independently and can be a hydrogen atom, an alkyl such as but not limited to a methyl, an ether such as but not limited to methyl ethyl ether, an alcohol such as but not limited to ethanol, a carboxylic acid such as but not limited to acetic acid, an aryl such as but not limited to benzene, an amino acid such as but not limited to serine or threonine, or a peptide such as but not limited to luetinizing hormone.
• R groups can be modified in order to increase the overall solubility of the complexes.
• N-heterocyclic carbenes that will be used to bind to Ag(I) are represented by but not limited to formulas 7-8:
• R 1-2 can be independently or non-independently represented by a halide, a proton, an alkyl, an ether, an alcohol, a nitro, a cyano, or a carboxylic acid
• R 3 _ 4 can be independently or non-independently represented by a hydrogen atom, an alkyl such as but not limited to a methyl, an ether such as but not limited to methyl ethyl ether, an alcohol such as but not limited to ethanol, a carboxylic acid such as but not limited to acetic acid, an aryl such as but not limited to benzene, an amino acid such as but not limited to serine or threonine, or a peptide such as but not limited to luetinizing hormone
• X can be represented by NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , PF 6 , BPh 4 , Cl, Br, and I.
• R 1-4 can vary independently and can be a hydrogen atom, an alkyl such as but not limited to a methyl, an ether such as but not limited to methyl ethyl ether, an alcohol such as but not limited to ethanol, a carboxylic acid such as but not limited to acetic acid, an aryl such as but not limited to benzene, an amino acid such as but not limited to serine or threonine, or a peptide such as but not limited to luetinizing hormone, and wherein X can be represented by NO 3 , OAc, SCN, BF 4 , OTf, SO 4 , PF 6 , BPh 4 , Cl, Br, and I.
• R groups can be modified for solubility purposes.
• preparations of the nanoparticles involves the use of large amounts of water combined with a small amount of an organic solvent, it is understood that the silver(I) metal complexes incorporated within the nanoparticles will form in the organic portion of the mixture in the case of some nanoparticles and in the hydrophobic core of the nanoparticles in the case of other nanoparticles. Therefore, the selected silver(I) metal complexes will need to be hydrophobic.
• the silver(I) N-heterocyclic carbenes as shown in formulas 9-13, have been prepared having hydrophobic substituent groups.
• the silver(I) N- heterocyclic carbenes as shown in formulas 14 and 15, are further examples wherein R 1 -R 4 represent the same or different hydrophobic alkyl and aryl substituent groups.
• Formulas 16-21 are further examples of hydrophobic silver(I) N-heterocyclic carbenes.
• a silver(I) complex as represented in formula 23 has been tested for preliminary anticancer activity against the ovarian cancer cell line NuTu- 19.
• Silver complex 23 was chosen because of its overall stability. This silver(I)-NHC has shown anticancer activity when tested for a period of 72 hours.
• R The functional groups, R, as seen in formula 27 serve to alter solubility properties of the complexes.
• the R group is an alcohol. Suitable alcohols include ethanol and propanol.
• n has a value between 1 and 200.
• Formulas 24-27 were found to almost immediately decompose in water at ambient temperature in light. It was also observed that formulas 24-27 exhibited poor stability in a physiological amount of sodium chloride. Decomposition of formulas 23-26 resulted in an active silver and imidazolium cation. Formulas 24 and 26 were shown to produce severe toxicity in rat models via IV tail injection.
• the method of treatment can be but is not limited to intravenous injection, intraperitoneal injection, inhalation, or oral ingestion.
• the drug can be dissolved in a suitable solvent.
• the choice solvent is typically a physiological saline solution. This solution can range from 0.5 to 1.0% sodium chloride in water because at this concentration the saline solution is of biological significance as it is isotonic with blood plasma.
• Another suitable solvent is dimethyl sulfoxide (DMSO).
• DMSO dimethyl sulfoxide
• Other biologically acceptable solvents are also acceptable.
• the inhalation method will involve nebulization of the drug, as the drug will be inhaled as an aerosol.
• the oral ingestion method includes ingestion of the drug as a pill, capsule, caplet or tablet.
• Formulation of the silver(I) metal complexes as a nanoparticle delivery system confers various clinical advantages.
• the formulation promotes slow leaching of the parent silver(I) metal complexes and active silver cation, thus providing a depot delivery of active drug.
• This slow-release effect allows for increased dosing intervals and increased patient compliance.
• these particles can be taken up by alveolar macrophages and delivered to the systemic circulation. Previous studies have shown that aggregate particles in the size range of 1- 5 ⁇ m can be phagocytized by macrophages, which subsequently migrate from the lung surface to the lymphatic system.
• the lymphatic system is intimately connected to the immune system as a whole, targeting of the silver(I) metal complexes drugs to the macrophages may offer benefits over traditional systemic delivery. If the immune system is targeted in this way, dose reduction is possible, yielding the same clinical outcomes as higher dosed oral or systemic type antimicrobials and eliminating potential dose-related side effects.
• the silver(I) metal complexes of the present invention can be used to recognize tumor- associated antigens and tumor specific antigens to deliver a therapeutic and cytotoxic agent to cancerous tissue and cells, while minimizing exposure of the cytotoxic agents to non-cancerous, healthy tissue and cells.
• Antibodies such as, for example, monoclonal antibodies that recognize tumor associated antigen or tumor specific antigen, are complexed with, for example, strepravidin and introduced into a patient. The antibody recognizes the tumor associated antigen and associates with is, thereby localizing the streptavidin in the tumor tissue.
• the silver(I) metal complexes, which have biotin bound thereto are introduced into the patient. The streptavidin binds the biotin and localizes the silver(I) metal complexes at the tumor tissue.

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